ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1515del (p.Phe506fs)

dbSNP: rs1583319050
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001011878 SCV001172256 pathogenic Hereditary cancer-predisposing syndrome 2019-09-10 criteria provided, single submitter clinical testing The c.1515delG pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1515, causing a translational frameshift with a predicted alternate stop codon (p.F506Sfs*89). An individual with Constitutional Mismatch Repair Deficiency (CMMRD) was homozygous for this alteration (Tesch VK et al. Front Immunol. 2018 Jul;9:1506). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001232897 SCV001405469 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-06-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This sequence change creates a premature translational stop signal (p.Phe506Serfs*89) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 30013564). ClinVar contains an entry for this variant (Variation ID: 819374).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280590 SCV001467799 pathogenic Hereditary nonpolyposis colon cancer 2020-12-30 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1515delG (p.Phe506SerfsX89) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251368 control chromosomes (gnomAD). c.1515delG has been reported in the literature in one homozygous individual affected with constitutional mismatch repair deficiency (Tesch_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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